Thioltransferase (glutaredoxin) mediates recovery of motor neurons from excitotoxic mitochondrial injury

Kenchappa, Rajappa S. ; Diwakar, Latha ; Boyd, Michael R. ; Ravindranath, Vijayalakshmi (2002) Thioltransferase (glutaredoxin) mediates recovery of motor neurons from excitotoxic mitochondrial injury Journal of Neuroscience, 22 (19). pp. 8402-8410. ISSN 0270-6474

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Official URL: http://www.jneurosci.org/content/22/19/8402.short

Abstract

Mitochondrial dysfunction involving electron transport components is implicated in the pathogenesis of several neurodegenerative disorders and is a critical event in excitotoxicity. Excitatory amino acid L-β-N-oxalylamino-L-alanine (L-BOAA), causes progressive corticospinal neurodegeneration in humans. In mice, L-BOAA triggers glutathione loss and protein thiol oxidation that disrupts mitochondrial complex I selectively in motor cortex and lumbosacral cord, the regions affected in humans. We examined the factors regulating postinjury recovery of complex I in CNS regions after a single dose of L-BOAA. The expression of thioltransferase (glutaredoxin), a protein disulfide oxidoreductase regulated through AP1 transcription factor was upregulated within 30 min of L-BOAA administration, providing the first evidence for functional regulation of thioltransferase during restoration of mitochondrial function. Regeneration of complex I activity in motor cortex was concurrent with increase in thioltransferase protein and activity, 1 hr after the excitotoxic insult. Pretreatment with α-lipoic acid, a thiol delivery agent that protects motor neurons from L-BOAA-mediated toxicity prevented the upregulation of thioltransferase and AP1 activation, presumably by maintaining thiol homeostasis. Downregulation of thioltransferase using antisense oligonucleotides prevented the recovery of complex I in motor cortex and exacerbated the mitochondrial dysfunction in lumbosacral cord, providing support for the critical role for thioltransferase in maintenance of mitochondrial function in the CNS.

Item Type:Article
Source:Copyright of this article belongs to Society for Neuroscience.
Keywords:Excitatory Amino Acid; Glutaredoxin; Mitochondria; Motor Neuron Disease; Glutathione; Brain; Complex I; Oxidative Stress
ID Code:40493
Deposited On:24 May 2011 13:58
Last Modified:17 May 2016 22:33

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